1-substituted amino-isoquinolines and nitrates thereof

ABSTRACT

DISCLOSED ARE COMPOUNDS OF THE CLASS OF SIOQUINOLINES SUBSTITUTED AT THE 1-POSITION BY AN AMINO FUNCTION BEARING A HYDROXY-ALKYL NITRATE MOIETY, E.G., 1-(5-HYDROXYPENTYL)AMINO-6,7-METHYLENE-DIOXYISOQUINOLINE NITRATE. THE COMPOUNDS HAVE VARIOUS PHARMACOLOGICAL ACTIVITIES IN ANIMALS ARE ARE USEFUL FOR EXAMPLE, AS ANTI-HYPERTENSIVE AGENTS, ANTI-ANGINAL AGENTS AND IN THE TREATMENT OF SHOCK. ALSO DISCLOSED ARE THE CORRESPONDING HYDROXY INTERMEDIATES WHICH ARE USEFUL IN PREPARATION OF THE NITRATES AND ALSO AS HYPTENSIVE AGENTS OR AS AGENTS IN THE TREATMENT OF SHOCK.

United States Patent I-SUBSTITUTED AMINO-ISOQUINOLINES AND NITRATES THEREOF William R. J. Simpson, Hanover, NJ., assignor to Sandoz-Wander, Inc., Hanover, NJ. No Drawing. Filed Dec. 7, 1970, Ser. No. 95,989 Int. Cl. (30711 35/36, 51/70 US. Cl. 260-288 R 8 Claims ABSTRACT OF THE DISCLOSURE Disclosed are compounds of the class of isoquinolines substituted at the 1-position by an amino function bearing a hydroxy-alkyl nitrate moiety, e.g., 1-(5-hydroxypentyl)- amino-6,7-methylene-dioxyisoquinoline nitrate. The compounds have various pharmacological activities in animals and are useful, for example, as anti-hypertensive agents, anti-anginal agents and in the treatment of shock. Also disclosed are the corresponding hydroxy intermediates which are useful in preparation of the nitrates and also as hypotensive agents or as agents in the treatment of shock.

This invention relates to isoquinoline derivatives, and more particularly to isoquinolines which are substituted at the 1-position by an amino function bearing a hydroxyalkyl nitrate moiety. The invention also relates to pharmaceutical methods and compositions utilizing said compounds. The invention further relates to corresponding hydroxyalkyl substituted isoquinolines useful as intermediates in preparation of said nitrates.

The compounds of the invention may be represented by the structural Formula I:

in V

R is from the group of (d) -CI-I (CH ),,ONO when R is (a) as above defined, (e) hydrogen, and (f) lower alkyl of 1 to 4 carbon atoms,

provided that one R (and only one) is other than hydrogen, that the sum of n and m does not exceed 6 and that the sum of n and y does not exceed 7, or

R and R together with the l-amino nitrogen attached to the isoquinoline ring form -N /NCH (CHz)r-NO n is 1 to 6, preferably 3 to 5, m is 0 to 4, y is 1 to 4,

zis1to4,and

each of Y, Y and Y" is hydrogen, lower alkoxy of 1 to 3 carbon atoms, e.g., methoxy or lower alkyl of 1 to 3 carbon atoms, e.g. methyl, or Y and Y' together form 3,778,440 Patented Dec. 11, 1973 methylenedioxy; provided that no more than 2 of Y, Y and Y" are lower alkyl; or a pharmaceutically acceptable non-toxic acid addition salt thereof.

A preferred method for preparation of the compounds of Formula I involves in a Step A reaction the nitration of the corresponding hydroxy compound of Formula H:

N-Rz

wherein Y, Y and Y" are as defined and R and R are the non-nitrate bearing hydroxyalkyl substituents corresponding to R and R respectively, i.e.:

n, m, y and z and Y, Y' and Y" are as defined.

The preparation of Compounds I by Step A involves a nitration reaction which may be carried out in a manner known per se for nitrating hydroxylakyl groups. A preferred method of conducting the nitration involves the reaction of a Compound II with nitric acid in presence of a carboxylic acid anhydride which is preferably of from 3 to 8 carbon atoms, more preferably acetic acid anhydride. The reaction may be suitably carried out in an organic solvent medium at temperatures in the range of from minus 70 C. to plus 50 C., preferably minus 5 C. to plus 20 C. The solvent medium for the reaction is preferably provided by employing a lower aliphatic carboxylic acid, e.g., acetic acid, although other well known organic solvents may be employed or the reaction may be carried out employing an excess of the carboxylic acid anhydride. The product Compound I may be isolated from the reaction mixture of Step A by working up by established procedures.

A preferred method for preparation of Compounds H involves a Step B reaction of a l-haloisoquinoline of Formula HI:

X (III) wherein Y, Y and Y" are as defined and X is halo from the group of chloro or bromo, preferably chloro, with a compound of Formula IV:

HIII-R:

wherein R and R are as defined.

The reaction of Step B is of known type and may be carried out in a conventional manner by subjecting a Compound III to reaction with the Compound IV at elevated temperatures which may be suitably in the range of 30 C. to 180 0., preferably 60 C. to 160 C. The reaction may be suitably carried out in an inert organic solvent which may be any of several of the well-known conventional solvents, preferably an aromatic solvent such as benzene. Another preferred solvent is isopropanol. Alternatively, the reaction may be initiated and/ or carried out in the inert liquid medium provided by employing an excess of Compound IV when the compound is liquid at the reaction temperature or by fusion of solid reactants. An acid binding agent such as sodium carbonate may be also employed to advantage in the reaction, if desired. The reaction product Compound II may be isolated from the reaction mixture of Step B by established procedures.

The compounds of Formulae III and IV are either known or may be prepared from known materials by established procedures, for example, as described for Compounds III by Anderson et al., J. Am. Pharm. Assoc. Sci. ed. 41,643-50 (1952). 1

Also within the scope of the novel compounds of the invention are pharmaceutically acceptable salts not materially affecting the pharmacological effect of the compounds of Formula I. Such salts include the acid addition salts, e.g., the methane sulfonate, hydronitrate, hydrosulfate, fumarate, hydrochloride and maleate. It is convenient to prepare the compounds of Formula I as a hydronitrate addition salt. Such salts may be the readily converted to the free bases by conventional procedures. In preparing the free bases from the acid addition salt, it is also convenient to employ a buffer system, e.g., a system comprising a 1:1 molar mixture of acetic acid and sodium acetate, followed by working up by conventional procedures. The free bases may be readily converted into the hydronitrate and other acid addition salts by established procedures.

The compounds of Formula I and their pharmaceutically acceptable acid addition salts are useful because they possess pharmacological activity in animals. In particular, the compounds of the Formula I, excluding those of the Formula 1(a) as hereinafter defined, are useful as antihypertensive agents as indicated by a lowering of blood pressure on intravenous administration to the anesthetized dog in the Cannulated Blood Vessel Test. Such compounds of the Formula I (excluding those of theh Formula 1(a)) are further useful as antianginal agents as indicated by efiecting coronary dilation in the anesthetized dog on intravenous administration and measurement of blood flow through the anterior descending branch of the left coronary artery and by effecting cerebral vasodilation in the anesthetized dog on intravenous administration.

The compounds of the Formula I having the Formula 1(a):

R R N 4 (C z) r-ONO:

wherein z is as defined and each R is alkoxy of 1 to 3 carbon atoms, as represented by the compound of Example 1 hereinafter, effect an increase in blood pressure and coronary dilation in the above-identified tests in the anesthetized dog. This unusual and desirable combination of effecting coronary dilation and an increase in blood pressure indicates that the compounds of the formula 1(a) are useful in the treatment of myocardial or hemorrhagic shock.

For the above uses, the compounds of the Formula I including Formula 1(a) may be combined with a pharmaceutically acceptable carrier, and such other conventional adjuvants as may be necessary, and administered orally in such forms as tablets, capsules, elixirs, suspensions and the like or parenterally in the form of an injectable solution or suspension. For the above-mentioned uses, the dosage administered will, of course, vary depending upon the compounds used, the therapy desired and the mode of administration. However, for use as anti-hypertensive agents, satisfactory results in general are obtained with the compounds of the Formula I (excluding those of the Formula 1(a) when administered at a daily dosage of from about 0.2 milligram to about 100 milligrams per kilogram of body weight, preferably given in divided doses 2 to 4 times a day, or in sustained release form. For most larger mamals, the administration of from about 16 milligrams to about 500 milligrams of the compound per day provides satisfactory results and dosage forms suitable for internal administration comprise from about 4 milligrams to about 250 milligrams of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent.

As anti-anginal agents, satisfactory results may be obtained when administered at a daily dosage of from 0.2 to 100 milligrams per kilogram of body weight, given as required or in divided doses or in sustained release form. For most large mammals a dosage of from 16 to 500 milligrams, pro re nata, provides satisfactory results. The compounds may also be used prophylactically in mammals to prevent or minimize angina attacks at a daily dosage of 16 to 500 milligrams, or in divided doses of from 4 to 25 0 milligrams.

For the treatment of myocardial or hemorrhagic shock the compounds of the Formula 1(a) may be administered to obtain effective results at a dosage of from 0.008 to milligrams per kilogram of animal body weight, pro re nata. For most mammals satisfactory results are obtained on the administration of from 0.6 to 200 milligrams, pro re nata. For use in the treatment of such shocks parental administration is usually preferred.

Some of the compounds of the Formula II employed as intermediates are known in the art. Various of the compounds of the Formula II which are not heretofore known may be represented by the following structural formulae:

Y '2 (II (8)) a 10 Y Y'l and Y Y N-R N-R l. i. wherein R5 iS each of Y Y: and Y is hydrogen or lower alkoxy of 1 to 3 carbon atoms provided that at least two of Y Y; and Y": are other than hydrogen; or Y and Y; together form methylenedioxy;

x is 2 to 6;

R is from the group of R is hydrogen, or R and R together with the l-amino nitrogen attached to the isoquinoline ring form each of Y Y' and Y" is hydrogen or lower alkoxy of 1 to 3 carbon atoms provided at least one is other than hydrogen, or Y and Y' together form methylenedioxy,

and n, R,,, y and z are as above defined and subject to the provisos on the sum of n and m and the sum of n and y previously given.

The compounds of the Formulae II(a) and II(b) are also useful as pharmaceutical agents. In particular, the compounds of the Formula II(a) and II(b), except those of the Formula II(c) hereinafter, are useful as hypotensive agents as indicated by a lowering of blood pressure in the anesthetized dog on intravenous administration.

The compounds of the Formula II(b) having the Formula II(c):

wherein R and z are as defined, as represented by the compound of Step A of Example 1 hereinafter, eifect coronary dilation and also effect as increase in blood pressure in the anesthetized dog in the above-identified tests for such indications. The compounds of the Formula H(c) are therefore also useful in the treatment of animals suffering from myocardial or hemorrhagic shock, and for the treatment of such shocks the compounds of the Formula II(c) are indicated as preferred over those of the Formula 1(a).

For the use of the compounds of the Formulae II(a) and II(b) (except those of the Formula II(c)) as hypotensive agents satisfactory results may be obtained when administered at a daily dose of from 0.4 milligram to 150 milligrams per kilogram of body weight. For most mammals the administration of from about 20 to 600 milligrams per day provides satisfactory results and dosage forms comprise from about 5 to 300 milligrams of the compounds in admixture with a solid or liquid carrier or diluent.

For the treatment of myocardial or hemorrhagic shock the compounds of the Formula II(c) may be effectively administered at a dosage of from 0.004 to 40 milligrams per kilogram of animal body weight, pro re nata. For most mammals satisfactory results are obtained on the administration of from 0.3 to 150 milligrams, pro re nata. For such usage the compounds of the Formula II(c) are preferably administered parenterally, e.g., intravenously.

The compounds of the Formulae II(a) and II(b) also form acid addition salts and those pharmaceutically aci ceptable acid addition salts of the compound of the For: mulae II(a) and II(b) are included within the scope of the pharmaceutically useful compounds of the Formulae II(a) and II(b) of the invention. Such salts include by way of illustration the hydrochloride, maleate and meth anesulfonate and may be formed from or converted to the sorresponding free base by conventional procedures.

For the above usages, oral administration with carriers may take place in such conventional forms as tablets, dispersible powders, granules, capsules, syrups and elixirs. Such compositions may 'be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatable preparation. Tablets may contain the active ingredient in admixture with conventional pharmaceutical excipients, i.e., inert diluents such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents, e.g., starch, gelatin and acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and talc. The tablets may be uncoated or coated by known techniques to delay disintegration and adsorption in the gastro-intestinal tract and thereby provide a sustained action over a longer period. Similarly, suspensions, syrups and elixirs may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation of such compositions, e.g., suspending agents (methylcellulose, tragacanth and sodium alginate), wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan mono-oleate) and preservatives (ethyl-p-hydroxybenzoate). Capsules may contain the active ingredients alone or admixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate and kaolin. Except for the use in the treatment of shocks the, preferred pharmaceutical compositions from the standpoint of preparation and ease of administration are solid compositions, particularly hard-filled gelatin capsules and tablets.

A representative formulation is a tablet prepared by conventional tabletting techniques and containing the following ingredients:

Ingredients: Weight (mg.) Compound of the Formula I 50 Tragacanth 10 Lactose 197.5 Corn starch 2 Talcum l5 Magnesium stearate 2.5

Ingredient: Weight (percent) Compound of Step A of Example 1 5.

Sodium chloride To make isotonic. Buffer agent To adjust pH. Ethanol, U.S.P 10 to 20. Propylene glycol 15 to 25. Water for injection 15 to 75.

In general, the compositions of the invention adapted for either oral or parenteral administration may contain 1% to by weight of the active ingredient in combination with the inert carrier, more usually 3% to 40%.

The following examples are given for the purpose of illustration only.

7 EXAMPLE 1 1- [4- (2-hydroxyethyl l-piperazino] -6,7-dimethoxyisoqninoline nitrate dimaleate -dlmaleate omo N (ii Hg Hz 0 N O 2 Step A.Preparation of 1-[4-(2hydroxyethyl)-1-piperazino]-6,7-dimethoxyisoquinoline: A mixture of 2.6 g. of l-chloro-6,7-dimethoxyisoquinoline and 6.0 g. of 2-hydroxyethylpiperazine is heated at 140 C. for 2 hours and then combined with 50 ml. of isopropanol and 2 g. of sodium carbonate. The resulting mixture is refluxed for 15 minutes, filtered, evaporated in vacuo to an oil which is purified by chromatography on silica gel to obtain 1-[4-(2 hydroxyethyl) 1 piperazino]-6,7-dimethoxyisoquinoline, M.P. 115-118" C.

Step B.--Preparation of l-[4 (2-hydroxyethyl)-1- piperazino]-6,7-dimethoxyisoquinoline nitrate dimaleate: A solution of 2.37 g. of 1-[4-(2-hydroxyethyl)-l-piperazino]-6,7-dimethoxyisoquinoline in 12 ml. of acetic acid is added dropwise to a stirred mixture of 4.3 ml. of acetic anhydride and 1.4 ml. of 90% nitric acid at a temperature of 5 C. The resulting mixture is stirred for minutes and then added to an excess of ice-cold aqueous ammonia solution. The resulting mixture is extracted with methylene chloride and the extract dried and evaporated in vacuo to an oil which is purified by chromatography on silica gel to obtain an amber oil of the free base of the title compound. This oil in an amount of 1.35 g. is dissolved in methylene chloride and 0.855 g. of maleic acid added. The resulting solution is filtered, evaporated to a small volume and the residue crystallized from methanol/diethyl ether to obtain 1-[4-(2-hydroxyethyl)-1- piperazino]6,7-dimethoxyisoquinoline nitrate dimaleate, M.P. 139 C. (decomp.).

EXAMPLE 2 1- S-hydroxypentyl) amino-6,7-methylenedioxyisoquinoline nitrate maleate Step A.--Preparation of 1 -(5 hydroxypentyl)amino- 6,7-methylenedioxyisoquinoline: A mixture of 1.8 g. of l-chloro-6,7-methylenedioxyisoquinoline and 5 g. of 5- hydroxypentylamine is heated at 140 C. for 5.5 hours. The resulting material is dissolved in methanol, sodium carbonate added and the resulting mixture refluxed for minutes. The resulting mixture is filtered and evaporated in vacuo to an oil which is dissolved in chloroform. The resulting solution is evaporated in vacuo and the residue purified by chromatography over silica gel. The resulting oily product is then crystallized from ethanol/ ethyl acetate and recrystallized from ethyl acetate/methanol to obtain 1-(5-hydroxypentyl)amino-6,7-methylenedioxyisoquinoline, M.P. l32.5134 C.

Step B.Preparation of 1-(5-hydroxypentyl) amino-6,7- methylenedioxyisoquinoline nitrate maleate: A solution of 0.835 g. of 1-(S-hydroxypentyl)amino-6,7-methylenedioxyisoquinoline and 1 m1. of acetic acid is added dropwise to a stirred mixture of 1.32 ml. of acetic anhydride and 0.44 ml. of nitric acid at a temperature of minus 3 C. The reaction mixture is stirred for about 20 minutes at about minus 3 C., and then added to an excess of ice-cold aqueous ammonia solution and twice extracted with ethyl acetate. The combined organic extracts are dried, filtered and evaporated in vacuo to an oil which is redissolved in chloroform. The resulting solution is passed through silica gel to obtain 0.965 g. of an oil of the free base of the above title compound. This oil is dissolved in methylene chloride and 0.5 g. of maleic acid is added. The resulting solution is filtered, evaporated to a small volume and diethyl ether added to crystallize a material which is then recrystallized from methanol/ diethyl ether to obtain 1-(S-hydroxypentyl)amino-6,7- methylenedioxyisoquinoline nitrate maleate, M.P. 138- EXAMPLE 3 Following the procedure of Example 2 the following compounds are similarly prepared:

(a) 1 [3 bis(2-hydroxyethyl)aminopropyl]amino- 6,7-dimethoxyisoquinoline.

(a-l) 1 [3 bis(2 hydroxyethyl)aminopropyl] amino 6,7 dimethoxyisoquinoline dinitrate dimaleate, M.P. 81 C. (decomp.).

(b) 1 [3 bis(2 hydroxyethyl)aminopropyl]amino- 6,7-methylenedioxyisoquinoline (recrystallized from ethanol).

(b-1) 1 [3 bis(2 hydroxyethyl)aminopropyl] amino 6,7 methylenedioxyisoquinoline dinitrate dimaleate, as an oil.

(0) 1 [4 (2 hydroxyethyl) 1 piperazino] 6,7- methylenedioxyisoquinoline.

(c1) 1 [4 (2 hydroxyethyl) 1 piperazino]-6,7- methylenedioxyisoquinoline nitrate dimaleate, M.P. 139 C. (decomp.) (crystallized from methanol/diethyl ether).

(d) 1 [3 bis(2 hydroxyethyl)aminopropyl]aminoisoquinoline.

(d-l) 1 [3 bis(2 hydroxyethyl)aminopropyl] aminoisoquinoline dinitriate dihydrochloride, M.P. 123.5- 126 C. (decomp.) (crystallized from methanol/isopropanol/diethyl ether).

(e) 1-[4-(2-hydroxyethyl-1-piperazino]-isoquinoline.

(er-1) 1 [4 (2 hydroxyethyl) 1 piperazino]-isoquinoline nitrate dihydrochloride, M.P. 173 C. (decom.).

(f) l (5 hydroxypentyl)amino-isoquinoline, M.P. 109110 C. (crystallized from ethyl acetate).

(f-l) l (5 hydroxypentyl)amino-isoquinoline nitrate hydronitrate, M.P. 121-122 C. (decomp.) (crystallized from methanol/diethyl ether).

What is claimed is: 1. A compound of the formula 9 R is from the group of (d) CH (-CH -ONO when R is (a) as above defined (e) hydrogen, and (f) alkyl of 1 to 4 carbon atoms,

R is hydrogen, -(CH CH or -(CH ONO provided that one R is other than hydrogen, that the sum of n and m does not exceed 6 and that the sum of n and y does not exceed 7,

n is 1 to 6,

m is to 4,

y is 1 to 4,

z is 1 to 4, and

each of Y, Y' and Y" is hydrogen, alkoxy of 1 to 3 carbon atoms, or alkyl of 1 to 3 carbon atoms, or Y and Y together form methylenedioxy, provided that no more than 2 of Y, Y and Y" are alkyl; or a pharmaceutically acceptable non-toxic acid addition salt thereof. 2. A compound of claim 1 having the formula:

wherein each of Y, Y and Y" is hydrogen, lower alkoxy or lower alkyl, or Y and Y together form methylenedioxy; provided that no more than 2 of Y, Y' and Y" are lower alkyl;

R and R together with the l-amino nitrogen attached to the isoquinoline ring form the group,

provided that both of Y and Y are not lower alkoxy while Y" is hydrogen when R and R form said group, or is from the group or:

10 and l (0) CH: 112) .N[- H2( Hz)y 2]: R is from the group of:

(d) -CH (CH ),',-ONO when defined; (e) hydrogen, and (f) lower alkyl, R is hydrogen, (CH CH or (CH ONO provided that one R is other than hydrogen, that the sum of n and m does not exceed 6 and that the sum of n and y does not exceed 7;

n is 1 to 6;

m is 0 to 4;

y is 1 to 4;

z is 1 to 4, or

a pharmaceutically acceptable non-toxic acid addition salt thereof.

3. A compound of claim 2 in which R is hydrogen.

4. A compound of claim 2 in which at least two of Y, Y and Y" are lower alkoxy or Y and Y together rep resent methylenedioxy.

5. A compound of claim 4 in which R is 7. The compound of claim 2 which is l (5 hydroxypentyl)amino-6,7-methylenedioxyisoquinoline nitrate.

8. The compound of claim 2 which is 1-[3-bis(2-hydroxyethyl)aminopropyl]amino 6,7 dimethoxyisoquinoline dinitrate.

References Cited UNITED STATES PATENTS R is as above 3,511,836 5/ 1970 Hess 260-25 6.4 3,517,005 6/1970 Cronin et a1. 260288 3,637,699 1/ 1972 Gabel et al 260-2564 3,637,700 1/ 1972 Gabel et al 2-60256.4 3,637,701 1/1972 Gabel et al. 260 -256.4 3,251,922 8/1941 Dickey 260--288 R 3,517,005 6/1970 Cronin 260-288 R DONALD G. DAUS, Primary Examiner US. Cl. X.R.

260--268 TR, 268 BQ, 283 R, 286 R, 289 R; 424250, 258 

